HMDH1_ASPFU
ID HMDH1_ASPFU Reviewed; 1130 AA.
AC Q4WHZ1;
DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 112.
DE RecName: Full=3-hydroxy-3-methylglutaryl-coenzyme A reductase 1 {ECO:0000303|PubMed:22106303};
DE Short=HMG-CoA reductase 1 {ECO:0000303|PubMed:22106303};
DE EC=1.1.1.34 {ECO:0000305|PubMed:22106303};
DE AltName: Full=Ergosterol biosynthesis protein hmg1 {ECO:0000303|PubMed:16110826};
GN Name=hmg1 {ECO:0000303|PubMed:22106303}; ORFNames=AFUA_2G03700;
OS Neosartorya fumigata (strain ATCC MYA-4609 / Af293 / CBS 101355 / FGSC
OS A1100) (Aspergillus fumigatus).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Fumigati.
OX NCBI_TaxID=330879;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC MYA-4609 / Af293 / CBS 101355 / FGSC A1100;
RX PubMed=16372009; DOI=10.1038/nature04332;
RA Nierman W.C., Pain A., Anderson M.J., Wortman J.R., Kim H.S., Arroyo J.,
RA Berriman M., Abe K., Archer D.B., Bermejo C., Bennett J.W., Bowyer P.,
RA Chen D., Collins M., Coulsen R., Davies R., Dyer P.S., Farman M.L.,
RA Fedorova N., Fedorova N.D., Feldblyum T.V., Fischer R., Fosker N.,
RA Fraser A., Garcia J.L., Garcia M.J., Goble A., Goldman G.H., Gomi K.,
RA Griffith-Jones S., Gwilliam R., Haas B.J., Haas H., Harris D.E.,
RA Horiuchi H., Huang J., Humphray S., Jimenez J., Keller N., Khouri H.,
RA Kitamoto K., Kobayashi T., Konzack S., Kulkarni R., Kumagai T., Lafton A.,
RA Latge J.-P., Li W., Lord A., Lu C., Majoros W.H., May G.S., Miller B.L.,
RA Mohamoud Y., Molina M., Monod M., Mouyna I., Mulligan S., Murphy L.D.,
RA O'Neil S., Paulsen I., Penalva M.A., Pertea M., Price C., Pritchard B.L.,
RA Quail M.A., Rabbinowitsch E., Rawlins N., Rajandream M.A., Reichard U.,
RA Renauld H., Robson G.D., Rodriguez de Cordoba S., Rodriguez-Pena J.M.,
RA Ronning C.M., Rutter S., Salzberg S.L., Sanchez M., Sanchez-Ferrero J.C.,
RA Saunders D., Seeger K., Squares R., Squares S., Takeuchi M., Tekaia F.,
RA Turner G., Vazquez de Aldana C.R., Weidman J., White O., Woodward J.R.,
RA Yu J.-H., Fraser C.M., Galagan J.E., Asai K., Machida M., Hall N.,
RA Barrell B.G., Denning D.W.;
RT "Genomic sequence of the pathogenic and allergenic filamentous fungus
RT Aspergillus fumigatus.";
RL Nature 438:1151-1156(2005).
RN [2]
RP IDENTIFICATION, AND FUNCTION.
RX PubMed=16110826; DOI=10.1080/13693780400029114;
RA Ferreira M.E., Colombo A.L., Paulsen I., Ren Q., Wortman J., Huang J.,
RA Goldman M.H., Goldman G.H.;
RT "The ergosterol biosynthesis pathway, transporter genes, and azole
RT resistance in Aspergillus fumigatus.";
RL Med. Mycol. 43:S313-S319(2005).
RN [3]
RP FUNCTION, AND INDUCTION.
RX PubMed=22106303; DOI=10.1073/pnas.1106399108;
RA Yasmin S., Alcazar-Fuoli L., Gruendlinger M., Puempel T., Cairns T.,
RA Blatzer M., Lopez J.F., Grimalt J.O., Bignell E., Haas H.;
RT "Mevalonate governs interdependency of ergosterol and siderophore
RT biosyntheses in the fungal pathogen Aspergillus fumigatus.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:E497-E504(2012).
RN [4]
RP MUTAGENESIS OF PRO-320.
RX PubMed=28931745; DOI=10.1098/rspb.2017.0635;
RA Zhang J., van den Heuvel J., Debets A.J.M., Verweij P.E., Melchers W.J.G.,
RA Zwaan B.J., Schoustra S.E.;
RT "Evolution of cross-resistance to medical triazoles in Aspergillus
RT fumigatus through selection pressure of environmental fungicides.";
RL Proc. R. Soc. B 284:0-0(2017).
RN [5]
RP FUNCTION, AND MUTAGENESIS OF PHE-262; SER-305 AND ILE-412.
RX PubMed=30940706; DOI=10.1128/mbio.00437-19;
RA Rybak J.M., Ge W., Wiederhold N.P., Parker J.E., Kelly S.L., Rogers P.D.,
RA Fortwendel J.R.;
RT "Mutations in hmg1, challenging the paradigm of clinical triazole
RT resistance in Aspergillus fumigatus.";
RL MBio 10:0-0(2019).
CC -!- FUNCTION: HMG-CoA reductase; part of the first module of ergosterol
CC biosynthesis pathway that includes the early steps of the pathway,
CC conserved across all eukaryotes, and which results in the formation of
CC mevalonate from acetyl-coenzyme A (acetyl-CoA) (PubMed:22106303,
CC PubMed:30940706). Hmg1 and hmg2 catalyze the reduction of
CC hydroxymethylglutaryl-CoA (HMG-CoA) to mevalonate (PubMed:22106303)
CC (Probable). The first module starts with the action of the cytosolic
CC acetyl-CoA acetyltransferase erg10B that catalyzes the formation of
CC acetoacetyl-CoA. The hydroxymethylglutaryl-CoA synthases erg13A and
CC erg13B then condense acetyl-CoA with acetoacetyl-CoA to form HMG-CoA.
CC The rate-limiting step of the early module is the reduction to
CC mevalonate by the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
CC reductases hmg1 and hmg2. Mevalonate is also a precursor for the
CC extracellular siderophore triacetylfusarinine C (TAFC)
CC (PubMed:16110826, PubMed:22106303) (Probable).
CC {ECO:0000269|PubMed:22106303, ECO:0000269|PubMed:30940706,
CC ECO:0000305|PubMed:16110826, ECO:0000305|PubMed:22106303}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(R)-mevalonate + CoA + 2 NADP(+) = (3S)-hydroxy-3-
CC methylglutaryl-CoA + 2 H(+) + 2 NADPH; Xref=Rhea:RHEA:15989,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:36464, ChEBI:CHEBI:43074,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.34;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10003,
CC ECO:0000305|PubMed:22106303};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:15991;
CC Evidence={ECO:0000305|PubMed:22106303};
CC -!- PATHWAY: Metabolic intermediate biosynthesis; (R)-mevalonate
CC biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3.
CC {ECO:0000269|PubMed:22106303}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000305};
CC Multi-pass membrane protein {ECO:0000255}.
CC -!- INDUCTION: Expression is induced during iron starvation.
CC {ECO:0000269|PubMed:22106303}.
CC -!- MISCELLANEOUS: Mutations of Phe-262, Ser-305, Pro-320 or Ile-412 are
CC associated to acquired resistance to azoles, clinical drugs used to
CC inhibit the activity and kill Aspergillus fumigatus cells during
CC infections. {ECO:0000269|PubMed:28931745, ECO:0000269|PubMed:30940706}.
CC -!- SIMILARITY: Belongs to the HMG-CoA reductase family. {ECO:0000305}.
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DR EMBL; AAHF01000008; EAL87464.1; -; Genomic_DNA.
DR RefSeq; XP_749502.1; XM_744409.1.
DR SMR; Q4WHZ1; -.
DR STRING; 746128.CADAFUBP00002026; -.
DR EnsemblFungi; EAL87464; EAL87464; AFUA_2G03700.
DR GeneID; 3506671; -.
DR KEGG; afm:AFUA_2G03700; -.
DR VEuPathDB; FungiDB:Afu2g03700; -.
DR eggNOG; KOG2480; Eukaryota.
DR HOGENOM; CLU_001734_0_0_1; -.
DR InParanoid; Q4WHZ1; -.
DR OMA; ILFFDCV; -.
DR OrthoDB; 907394at2759; -.
DR UniPathway; UPA00058; UER00103.
DR Proteomes; UP000002530; Chromosome 2.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IBA:GO_Central.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005778; C:peroxisomal membrane; IBA:GO_Central.
DR GO; GO:0004420; F:hydroxymethylglutaryl-CoA reductase (NADPH) activity; IBA:GO_Central.
DR GO; GO:0015936; P:coenzyme A metabolic process; IEA:InterPro.
DR GO; GO:0006696; P:ergosterol biosynthetic process; IBA:GO_Central.
DR GO; GO:0008299; P:isoprenoid biosynthetic process; IBA:GO_Central.
DR GO; GO:1900551; P:N',N'',N'''-triacetylfusarinine C biosynthetic process; IMP:AspGD.
DR GO; GO:0016126; P:sterol biosynthetic process; IBA:GO_Central.
DR CDD; cd00643; HMG-CoA_reductase_classI; 1.
DR Gene3D; 1.10.3270.10; -; 1.
DR Gene3D; 3.30.70.420; -; 1.
DR Gene3D; 3.90.770.10; -; 1.
DR InterPro; IPR025583; HMG-CoA_N_dom.
DR InterPro; IPR002202; HMG_CoA_Rdtase.
DR InterPro; IPR023074; HMG_CoA_Rdtase_cat_sf.
DR InterPro; IPR023076; HMG_CoA_Rdtase_CS.
DR InterPro; IPR004554; HMG_CoA_Rdtase_eu_arc.
DR InterPro; IPR023282; HMG_CoA_Rdtase_N.
DR InterPro; IPR009023; HMG_CoA_Rdtase_NAD(P)-bd_sf.
DR InterPro; IPR009029; HMG_CoA_Rdtase_sub-bd_dom_sf.
DR InterPro; IPR000731; SSD.
DR PANTHER; PTHR10572; PTHR10572; 1.
DR Pfam; PF00368; HMG-CoA_red; 1.
DR Pfam; PF13323; HPIH; 1.
DR Pfam; PF12349; Sterol-sensing; 1.
DR PRINTS; PR00071; HMGCOARDTASE.
DR SUPFAM; SSF55035; SSF55035; 1.
DR SUPFAM; SSF56542; SSF56542; 1.
DR TIGRFAMs; TIGR00533; HMG_CoA_R_NADP; 1.
DR PROSITE; PS00066; HMG_COA_REDUCTASE_1; 1.
DR PROSITE; PS00318; HMG_COA_REDUCTASE_2; 1.
DR PROSITE; PS01192; HMG_COA_REDUCTASE_3; 1.
DR PROSITE; PS50065; HMG_COA_REDUCTASE_4; 1.
DR PROSITE; PS50156; SSD; 1.
PE 1: Evidence at protein level;
KW Endoplasmic reticulum; Glycoprotein; Lipid biosynthesis; Lipid metabolism;
KW Membrane; NADP; Oxidoreductase; Reference proteome; Steroid biosynthesis;
KW Steroid metabolism; Sterol biosynthesis; Sterol metabolism; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..1130
FT /note="3-hydroxy-3-methylglutaryl-coenzyme A reductase 1"
FT /id="PRO_0000454150"
FT TOPO_DOM 1..46
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 47..67
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 68..242
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 243..263
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 264..270
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 271..291
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 292..296
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 297..317
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 318..366
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 367..387
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 388..389
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 390..410
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 411..476
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 477..497
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 498..601
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 602..622
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 623..1130
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT DOMAIN 242..415
FT /note="SSD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00199"
FT REGION 1103..1130
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 792
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 926
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 1002
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 1098
FT /note="Proton donor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10003"
FT BINDING 798..804
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT BINDING 859..861
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT BINDING 886..894
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT BINDING 955..957
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT BINDING 1097..1098
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT BINDING 1102..1103
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT CARBOHYD 148
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT MUTAGEN 262
FT /note="Missing: Contributes to acquired resistance to
FT azoles."
FT /evidence="ECO:0000269|PubMed:30940706"
FT MUTAGEN 305
FT /note="S->P: Contributes to acquired resistance to azoles."
FT /evidence="ECO:0000269|PubMed:30940706"
FT MUTAGEN 320
FT /note="P->L: Contributes to acquired resistance to azoles."
FT /evidence="ECO:0000269|PubMed:28931745"
FT MUTAGEN 412
FT /note="I->S: Contributes to acquired resistance to azoles."
FT /evidence="ECO:0000269|PubMed:30940706"
SQ SEQUENCE 1130 AA; 121271 MW; 57244799A9732C4C CRC64;
MATSLITRKL RSAEATNDVE PGWLKRQVTG VLQSISSHAC QHPIHTIVVI ALLASTTYVG
LLEGSLFDSV RNSRNIAGQV DVDTLLQGSR NLRLGESTSW KWQVEDSLAS QDYTGVNHLA
LTTFIFSDSL SKSSSIAPAA TELPIPSNAS AQPVPFTPNL FSPFSHDSSL AFTLPFDQVP
QFLKAVQEIP DTSSDEDDGE QKKWIMRAAR GSAYGSGGAI KLWLADAWGS FVDLIKHAET
IDIVIMTLGY LSMHLSFVSL FFSMRRLGSN FWLAATVLFS GVFAFLFGLL VTTKLGVPIN
VLLLSEGLPF LVVTIGFEKP IILTRAVLTA AADNRGRAGQ ASSSTTKSIQ DSIQTAIKEQ
GFEIIRDYCI EIAILIAGAA SGVQGGLRQF CFLAAWILFF DCVLLFTFYT TILCIKLEIN
RIKRHITLRK ALEEDGITHR VAENVASSND WPLTESESSN KTSIFGRKLR SSSVRRFKIL
MVGGFVLVNV VNLSTIPFRD SSQGAGLPLL SRVSNVFAPT PIDPFKVAEN GLDSIYVSAK
SQMMETVVTV IPPIKYKLEY PSVYYAALGE SRTFDIEYTD QFLDAVGGRV IESLLKSIED
PIISKWIIAA LTLSIILNGY LFNAARWSIK EPEVAPVPAA PTVAVVEAKK EYPKIDLNPD
TPKRSLEECE AFLKEKRAAY LSDEELIELS LRGKIPGYAL EKTMENEDLM SRVDAFTRAV
KIRRAVVART PATSAITGSL ECSKLPYKDY NYTLVHGACC ENVIGYLPLP LGVAGPLTID
GQSYFIPMAT TEGVLVASTS RGAKAINAGG GAVTVLTGDG MTRGPCVGFP TLARAAAAKV
WIDSEEGRSI LTAAFNSTSR FARLQHLKTA LAGTYLYIRF KTTTGDAMGM NMISKGVEKA
LHVMATECGF DDMATISVSG NFCTDKKAAA INWIDGRGKS VVAEAIIPGD VVRSVLKSDV
NALVELNTSK NLIGSAMAGS VGGFNAHASN IVTAVFLATG QDPAQNVESS SCITTMRNLN
GNLQIAVSMP SIEVGTIGGG TILEAQSAML DMLGVRGSHP TNPGDNARQL ARIVAAAVLA
GELSLCSALA AGHLVRAHMA HNRSAATTRT STPVSAAVSA ARGLTMSSSE
